Extended Follow-Up of Chronic Immune-Related Adverse Events Following Adjuvant Anti–PD-1 Therapy for High-Risk Resected Melanoma

This cohort study examined the incidence, characteristics, and long-term outcomes of chronic immune-related adverse events from adjuvant anti–programmable cell death-1 for advanced and metastatic melanoma at 6 institutions in the US and Australia.


Introduction
Immune checkpoint inhibitors (ICIs) have become the preferred first-line treatment for advanced melanoma and produce durable antitumor responses in approximately 50% of patients. 1,2 ICIs targeting programmed death-1/ligand-1 (PD-1/PD-L1) prolong recurrence-free survival (RFS) when used as adjuvant therapy. [3][4][5] Anti-programmed cell death-1 (anti-PD-1) also causes widespread T-cell activation and results in autoimmune side effects involving multiple organs, termed immunerelated adverse events (irAEs). While most severe irAEs are acute and resolve with glucocorticoids, we recently reported that up to 43% of irAEs persist for at least 12 weeks following therapy cessation in patients with melanoma treated with adjuvant anti-PD-1. 6,7 Given the expanding use of anti-PD-1 across various tumor types, it is imperative to further assess its long-term effects, which have not been well defined. To address this gap, we conducted a large, multicenter cohort study with extended follow-up in patients with chronic irAEs from adjuvant anti-PD-1 therapy. This study aimed to determine the incidence, characteristics, and long-term outcomes, including resolution vs persistence, of chronic irAEs from adjuvant anti-PD-1.

Methods
This cohort study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline. Institional review board or ethics committee approval was obtained from each institution, and informed consent was waived because patient data were deidentified.
Retrospective deidentified data were collected from 6 participating academic medical centers in the US and Australia. Patients who received at least 1 dose of adjuvant anti-PD-1 were included.
Those without evaluable follow-up for at least 18 months following treatment cessation were excluded. Patient demographics (melanoma subtype, comorbidities, genetic mutation status, and stage), treatment details (dose, frequency, duration, and reason for discontinuation), and disease recurrence details were collected from the electronic medical record from each institution. Type, grade, duration, treatment, and resolution details of acute, delayed, and chronic irAEs were noted. 8 Acute irAEs were defined as those arising during treatment, delayed irAEs as those arising within 6 months after treatment cessation, and chronic irAEs as those extending at least 3 months after treatment cessation (Figure). In total, 318 patients were included. Of these, 304 patients were  included with extended follow-up from our prior publication, 7 and 14 were patients who were not included in the original publication but met the inclusion criteria from this study. Patients from the original cohort without a minimum evaluable follow-up duration of 1.5 years after treatment cessation were excluded.

Statistical Analysis
Descriptive statistics were used to analyze categorical and continuous variables. The IQR was calculated by subtracting the first quartile, the RFS or OS value below which 25% of the data fell, from the third quartile, the RFS or OS value above which 25% of the data fell. The start time for RFS and OS was the date of anti-PD-1 initiation. Kaplan-Meier curves assessed survival using GraphPad version 9.5.1 (GraphPad Prism). Wilson score intervals were used to calculate CIs for proportions.

Results
Of the 318 patients included in this study, the median (

JAMA Network Open | Oncology
Immune-Related Adverse Events Following Adjuvant Anti-PD-

JAMA Network Open | Oncology
Immune-Related Adverse Events Following Adjuvant Anti-PD- were ongoing (Figure and

Discussion
In this cohort study of 318 patients treated with adjuvant anti-PD-1, chronic irAEs were common and often persisted long-term, although many chronic, nonendocrine irAEs eventually resolved. With at least 18 months of follow-up, 35.4% of patients experienced resolution of their chronic irAEs (including nearly half of nonendocrine irAEs), increased from our previous study showing that 14.4% of chronic toxic effects resolved with at least 6 months follow-up. While endocrine toxic effects (adrenal insufficiency, hypophysitis, and thyroiditis or hypothyroid) were more likely to become chronic and persist at last follow-up than nonendocrine toxic effects, other more symptomatic irAEs persisted at low rates individually, including cutaneous, rheumatologic, oral, and ocular events.
We and others have previously speculated whether chronic irAEs represent smoldering autoimmunity vs a burnout phenotype, where all the relevant cells have been destroyed or damaged, leading to continued symptoms. 9 The resolution of some chronic irAEs, as well as the flares occurring with retreatment (32.4%) suggest some patients have ongoing inflammation. The persistent nature of irAEs, particularly endocrinopathies, suggests that permanent damage may occur in some patients. For this population, rechallenge with a lower risk of irAEs may be possible (although some still flare). 10 Further research should aim to identify patients that are predisposed to persistent toxic effects.

Limitations
This study had limitations. Review of toxic effects and adverse events using clinical data and notes may lack the fidelity of formal clinical trial adverse event reporting. Documentation may not mention every toxicity in every note, thus lowering the fidelity of the resolution date for individual patients.
While most patients overlap with our prior study, the departure of 1 investigator from their prior institution resulted in slightly distinct patient populations from our previous study. RFS analysis between patients with and without chronic irAEs is highly likely to suffer from time-dependent bias.

Conclusions
Insights into the long-term impact of adjuvant anti-PD-1 therapy are crucial to optimize patient outcomes as these agents are used across different tumor types. The high prevalence of chronic irAEs suggests the importance of considering the risk-benefit ratio when initiating adjuvant therapy and the need for prolonged monitoring and proactive management of irAEs.